The goal of this contract is to provide support of the National Toxicology Program (NTP) hazard assessment activities targeted toward the prevention of diseases or adverse effects caused by environmental exposure to chemical or physical agents. An overall goal is for the National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) and the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) to assume a greater leadership role in promoting research, development, translation, validation, and regulatory acceptance of alternative test methods. The NICEATM-ICCVAM five-year plan builds on the ICCVAM mission of facilitating the development, validation, and regulatory acceptance of new and revised regulatory test methods that reduce, refine, and replace the use of animals in testing while maintaining and promoting scientific quality and the protection of human health, animal health, and the environment. The mission, vision, and strategic priorities will help NICEATM and ICCVAM achieve greater progress and inform the public of their plans and approaches. The plan also builds on the NTP's Roadmap for the 21st Century that includes the goal of developing and validating improved testing methods and, where scientifically feasible, to ensure that these methods reduce, refine, or replace the use of animals. The Roadmap also specifies that activities and assays developed under the NTP Roadmap will be conducted in cooperation and consultation with ICCVAM to maximize their value to regulatory agencies. U.S. regulatory agencies are charged with protecting human and animal health and the environment. As part of this mission, agencies need to determine whether adverse effects might result from exposures to substances such as pesticides, consumer products, medicines, medical devices, workplace chemicals, food additives, or to contaminants in air, food, or water. Many of the current test methods for evaluating hazard and risk assessments from exposure to such substances use laboratory animals. Federal agencies require that all test methods should be based on sound science. According to the ICCVAM Authorization Act of 2000, new, revised, and alternative test methods must be determined to be valid for their proposed use before agencies can adopt them for regulatory purposes. Validation is required to determine if the use of an alternative test method, compared to current methods or approaches, can provide equal or better protection of human and animal health and the environment. In the United States, the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) coordinates interagency issues on alternative toxicological test method development, validation, regulatory acceptance, and national and international harmonization. The committee is responsible for coordinating Federal interagency technical evaluations of new, revised, and alternative safety testing methods and forwarding test method recommendations to U.S. Federal agencies. The National Institute of Environmental Health Sciences originally established ICCVAM in 1997. In 2000, ICCVAM was established by law as a permanent interagency committee of the National Institute of Environmental Health Sciences under the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods. ICCVAM is composed of representatives from the 15 U.S. Federal regulatory and research agencies that require, use, or generate toxicological testing data and information. NICEATM administers ICCVAM and provides scientific and operational support for ICCVAM activities. NICEATM also conducts and coordinates international validation studies to evaluate the usefulness and limitations of potential new alternative test methods. NICEATM and ICCVAM work together to evaluate and promote the validation and regulatory acceptance of scientifically valid toxicological test methods based on sound science that will protect human and animal health and the environment, while reducing, refining (decreasing pain and distress), and replacing animal use where scientifically feasible. NICEATM and ICCVAM provide an essential framework for translating advances in science and technology into standardized and adequately validated safety testing methods that can be used to protect and advance public health. Since its establishment in 1997, ICCVAM has coordinated or contributed to the evaluation of 27 alternative test methods that have been accepted or endorsed by national and international authorities. The types of safety testing and available alternatives include: eye irritation and injury, acute systemic toxicity, dermal absorption, dermal corrosivity and irritation, allergic contact dermatitis, pyrogenicity, and vaccine potency. The alternative methods accepted by Federal agencies include 17 non-animal methods and 10 methods that use fewer animals and/or provide for refinement by reducing or avoiding potential discomfort. Most of the in vitro methods do not require the use of animals when positive results are obtained. Recommendations for additional alternatives for allergic contact dermatitis and ocular irritation are in development. In response to requests from the Appropriations Committees of the U.S. House of Representatives and U.S. Senate, ICCVAM and NICEATM prepared a five-year plan to describe goals and objectives for the years 2008 through 2012. This plan was developed in conjunction with Federal agency program offices and describes how NICEATM and ICCVAM will promote the research, development, translation, validation, and regulatory acceptance of alternative test methods that reduce, refine, and replace the use of animals in testing while maintaining scientific quality and protecting human health, animal health, and the environment. The plan identified four key challenges that NICEATM and ICCVAM will address in conjunction with agency programs. The first challenge is to identify priority toxicity testing areas for the next five years and to conduct and facilitate activities in those areas. Currently, the four highest priority areas are ocular toxicity, dermal toxicity, acute systemic toxicity, and biologics potency and safety testing. These are based on the potential for these tests to cause animal pain and distress and the fact that these are the most commonly conducted safety tests. Other priority areas include immunotoxicity, endocrine disruptors, pyrogenicity, reproductive and developmental, and chronic toxicity/carcinogenicity testing. The second challenge is to identify and promote research initiatives that are expected to support future development of innovative alternative test methods. These new methods might incorporate techniques such as high throughput screening, computer modeling, informatics, and biomarkers. The third challenge is for NICEATM and ICCVAM to foster the acceptance and appropriate use of alternative test methods through outreach and communication. This will be accomplished by sponsoring and participating in workshops, NICEATM-ICCVAM website communications, and the development and publication of standardized test method protocols. Lastly, ICCVAM and NICEATM will develop partnerships and strengthen interactions with stakeholders to facilitate meaningful progress. These efforts are expected to facilitate research, development, translation, validation and regulatory acceptance of alternative methods that will reduce, refine, and replace animal use while maintaining scientific quality and the protection of human health, animal health, and the environment. In June 2009, ICCVAM and NICEATM released an Implementation Plan for the NICEATM-ICCVAM Five-Year Plan. This working document describes how ICCVAM and NICEATM are implementing the strategies outlined in the Five-Year Plan and includes goals, specific objectives, and planned activities for implementation. The Implementation Plan also describes NICEATM and ICCVAM accomplishments since February 2008 that relate to the goals and objectives outlined in the Implementation Plan. NICEATM and ICCVAM recently created an alternative test methods milestones page on the NICEATM-ICCVAM website to provide a comprehensive overview of available alternative methods and a quick summary of current validation and evaluation activities, (http:// http://iccvam.niehs.nih.gov/methods/milestones.htm.). The page provides a comprehensive summary of the status of ongoing and completed NICEATM-ICCVAM alternative test method evaluation projects and projects to which NICEATM, ICCVAM, and agency scientists are contributing. The page also provides timelines for each project with links to more detailed information and relevant documents. Additional information about NICEATM and ICCVAM test method evaluation activities can be found at http://iccvam.niehs.nih.gov/. On April 27, 2009, representatives of the United States, the European Union, Canada, and Japan signed a Memorandum of Cooperation for International Cooperation on Alternative Test Methods (ICATM). The agreement provides a framework for enhanced international cooperation, collaboration, and communication in three critical areas: (1) test method validation studies, independent peer review of the validation status of test methods, and the development of harmonized formal test method recommendations for regulatory authorities The initial participating validation organizations are the NICEATM and ICCVAM, the Japanese Center for the Validation of Alternative Methods (JaCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Environmental Health Science and Safety Bureau within Health Canada. The cooperation among these organizations facilitated by this agreement is expected to accelerate international adoption of scientifically valid alternative test methods. NICEATM and ICCVAM convened an international independent scientific peer review panel in 2008 and 2009 to review several new versions and applications of the murine local lymph node assay (LLNA), an alternative test method for assessing the allergic contact dermatitis potential of chemicals and products. ICCVAM originally evaluated the scientific validity of the LLNA in 1998. U.S. Federal agencies accepted the ICCVAM recommendations that the LLNA was a valid substitute for the current guinea pig test method used to assess the allergic contact dermatitis and that it could be used to evaluate most but not all types of substances. ICCVAM also concluded that the LLNA has many advantages over the traditional test methods, including using fewer animals, eliminating the potential discomfort that can occur from substances that are sensitizers, and providing dose-response information. The LLNA was subsequently incorporated into national and international test guidelines for the assessment of skin sensitization. Accidental eye injury is a leading cause of visual impairment in the U.S., and many of these injuries occur due to contact with workplace or household chemicals. According to the National Institute of Occupational Safety and Health (NIOSH), each day about 2000 U.S. workers have a job-related eye injury that requires medical treatment. Even more eye injuries occur in the home; with about 125,000 eye injuries a year caused by accidents involving common household products such as oven cleaner and bleach (source, American Academy of Ophthalmology). Federal agencies require safety testing to determine whether consumer products or other substances may cause temporary or permanent damage to the eye. In October 2003, the U.S. Environmental Protection Agency (EPA) nominated four in vitro ocular toxicity test methods for evaluation as potential screening methods for eye corrosion or severe irritation. Ocular safety testing is one of ICCVAM's top four priorities because it is one of the four most common safety tests required and therefore involves significant number of animals. Such testing also has the potential to cause significant unrelieved pain and distress when chemicals and products cause eye damage. In 2008, two ICCVAM-recommended in vitro safety testing methods, the bovine corneal opacity and permeability (BCOP) and isolated chicken eye (ICE) test methods, were accepted by U.S. Federal agencies for identifying substances with the potential to cause severe or permanent damage to eyes without using live animals. The OECD Council formally adopted TGs for these test methods in 2009, with the BCOP described in TG 437 and the ICE in TG 438. These methods can now be used worldwide to identify substances that may cause severe or irreversible eye damage. Positive results can be used for hazard classification without the need to use live animals, thereby avoiding the pain and distress that may have resulted if animals had been required. NICEATM and ICCVAM organized an international independent scientific peer review panel that met in May 2009 to evaluate nine alternative methods and strategies for ocular safety testing. These included: The routine use of topical anesthetics, systemic analgesics, and humane endpoints to avoid and minimize pain and distress during in vivo ocular irritation testing. The use of the BCOP, the Cytosensor(R) Microphysiometer (CM), the ICE, the isolated rabbit eye, and the hen's egg test chorioallantoic membrane test methods for identifying moderate and mild ocular irritants and for identifying substances that do not cause sufficient eye injury to require ocular hazard labeling (non-labeled category). The in vivo low volume eye test. Non-animal testing strategies using the BCOP, CM, and/or EpiOcular test methods to assess the eye irritation potential of antimicrobial cleaning products and to determine their appropriate U.S. Environmental Protection Agency ocular hazard classification. Highlights of the Panel's conclusions and recommendations include: Topical anesthetics and systemic analgesics should routinely be used prior to all in vivo ocular irritancy testing. The Panel recommended an enhanced protocol of specific pain-relieving drugs and schedule of administration to effectively avoid or minimize discomfort. The BCOP and CM test methods could be used as screening tests to identify some products and substances that would not require hazard labeling for eye irritation. These methods will now be recommended for use in a bottom-up testing approach to identify substances that are not expected to cause sufficient injury to require classification as an ocular irritation hazard. Proposed non-animal testing strategies using three in vitro test methods to assess the eye irritation potential of antimicrobial cleaning products for EPA ocular hazard classification and labeling purposes appear promising. The Panel recommended that studies should be conducted to further characterize the in vitro test methods and that testing strategies should be designed in coordination with ICCVAM.